We propose to study the cellular activation and conditions of antigen presentation which result in human in vitro responses to Cryptococcus neoformans. Cryptococci are ubiquitous, encapsulated yeast which cause meningitis and disseminated infection in immunocompromised and occasional normal hosts. Based on clinical observation, hosts with defective cellular responses are at greatest risk for serious infection. The identity of the cells responding to this infection and their function in man are unknown. We have examined lymphocyte proliferative responses to this organism in normal humans and patients with cryptococcosis. First, we believe that changes in kinetics and magnitude of response we have observed in patients following therapy may correlate with outcome of the disease. Second, most normal individuals without known exposure to cryptococci show significant proliferation to the organism. Our preliminary data suggest this response is T cell and antigen-presenting cell dependent. The ability of normal lymphocytes to respond in vitro will allow us to define the cellular interactions, factor production, B cell differentiation, and effects of excess antigen during the response. We hope that in doing so, we will understand the requirements for generation of activated, antigen specific T cells and eventually their role in recovery from this disease. With the increasing population at risk and inadequacy of our current therapy, specific augmentation of immune responses in susceptible hosts may be a feasible alternative approach. The studies proposed here could provide some of the information necessary for this approach.